END STAGE RENAL DISEASE IN BLACKS

Question. End-stage renal disease due to hypertension is a major health problem among Black Americans. In fact, I understand that the incidence rate of End-stage renal disease with a diagnosis or cause of hypertension was 6.5 times greater in blacks than whites. What is known about the prospects for reducing End-stage renal disease by controlling hypertension?

Answer. Studies at a George M. O'Brien Kidney and Urology Research Center have shown that Blacks are twice as likely as Whites to demonstrate progression towards renal failure, despite good blood pressure control. The findings strongly point to the need for early detection of hypertension and more creative ways to treat it. This is especially important for individuals who are at high risk, and are thus susceptible to hypertension and renal damage. Studies are in progress which may further the understanding of the consequences of hypertension. These include interactions between angiotensin II and norepinephrine, and hormonal interaction in control of sodium chloride reabsorption. Both studies involve the use of special animal models, and are expected to yield new insights into the causes and possible outcomes of hypertensive renal disease.

OSTEOPOROSIS DRUG

Question. During the past year there has been considerable media coverage of a two year industry supported study of more than four hundred post-menopausal women that showed that administration of the drug "etidronate" for fourteen days followed by calcium for 76 days reversed bone loss. Has your Institute evaluated this treatment? What is your research agenda in the area of Osteoporosis?

Answer. NIDDK provides major support for biomedical research on osteoporosis. Hormones are major factors in the regulation of bone formation and bone loss. As the institute with lead responsibility for endocrine (hormone) research, the NIDDK plays a pivotal role in supporting studies of bone-active hormones and growth factors. The NIDDK also supports a large body of research into calcium absorption and bioavailability as well as research aimed at understanding how vitamin D affects bone. Although NIDDK has not evaluated etidronate therapy, previous research supported by the Institute on the effects of the closely related pyrophosphate was instrumental in the development of bisphosphonates such as etidronate. Similarly, NIDDK anticipates other novel therapies will arise from its ongoing basic research on hormones and growth factors which regulate bone formation. For example, NIDDK is supporting a new clinical trial evaluating parathyroid hormone in the treatment strategy for osteoporosis.

The NIDDK recently sponsored a Consensus Development Conference on the "Diagnosis and Management of Asymptomatic Primary Hyperparathyroidism.' The conference established guidelines for detection and prevention of silent organ damage, particularly progressive bone loss, in this disorder which affects 100,000 new patients each year in the United States. The NIDDK is among those NIH institutes supporting the Postmenopausal Estrogen/Progestin

Intervention clinical trial, which will provide important data on the risks and benefits of the most effective measure to prevent osteoporosis. NIDDK has joined with NIAMS in issuing two new RFAs soliciting basic and clinical research on osteoporosis and expects to expand what already constitutes a major portfolio of research in this area.

GENETICS OF KIDNEY DISEASE

Question. Doctor, this past year, we heard about the identification of the gene that is responsible for causing Alport Syndrome. What can you tell us about this finding, and what are its implications?

Answer. NIDDK investigators at the University of Utah School of Medicine have identified the gene and mutations responsible for the glomerular basement membrane defect which causes the Alport syndrome, to the chromosomal region Xq22. This represents the first cloning of a gene for any kidney disease, as well as the first example of a genetic glomerular basement membrane defect resulting in kidney disease. Until now, the lack of satisfactory markers for Alport syndrome has greatly hampered diagnosis and may have resulted in substantial underdiagnosis. Therefore, the true incidence and prevalence of Alport syndrome may only be known when systematic searches using reliable diagnostic markers are performed. In addition to improving diagnostic efforts, both in Alport syndrome as well as in other kidney diseases, the gene isolation and determination of specific mutations has implications for future treatment and/or prevention of the disease. addition, knowledge of the identity of the defective gene opens the possibility for gene therapy in which the effect of a defective gene could be directly masked. Research can focus into the design of appropriate therapeutic strategies, since it may now be possible to devise forms of effective treatment, or even gene replacement therapy, for the serious forms of Alport syndrome.

POLYCYSTIC KIDNEY DISEASE

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Question. Over a half million Americans have polycystic kidney disease. What is your Institute doing to help combat this serious disease?

Answer. The NIDDK has been working closely with the lay and scientific community interest in Polycystic Kidney Disease (PKD) to promote research and to increase the basic knowledge on all aspects of the disease. It is an inherited disorder which affects 500,000 Americans, and 7,000 new patients are recognized each year. It ranks first among the inherited and congenital conditions leading to end-stage renal disease and ranks fourth (behind kidney disease of diabetes mellitus, hypertension and glomerulonephritis) as a primary cause of end-stage renal disease and as a basic diagnosis among newly identified end-stage renal disease patients. Males and females are affected equally, and its worldwide distribution appears to demonstrate that it affects all races. To address these issues a Request for Research Grant Applications was issued earlier this year, inviting investigations directed at defining and further characterizing the etiology and pathogenesis of PKD. The deadline for receipt of applications is April 25, 1991. It is anticipated

that given the sophisticated research technology currently available, coupled with possible applications of emerging new knowledge, major progress can be attained in this area in the near future.

KIDNEY DISEASE AND HYPERTENSION IN BLACKS

Question. We understand from your opening statement that NIDDK has a plan for a pilot study on kidney disease and hypertension in blacks. Can you tell us more about it?

Answer. A Request for Applications for a pilot study on "Kidney Disease and Hypertension in Blacks" will be shortly released by NIDDK. The purpose of this pilot study is to test the feasibility of conducting a full-scale randomized clinical trial on the best approach to therapy for lowering high blood pressure in persons with chronic renal failure due to hypertension. Since endstage renal disease in hypertension is 6 1/2 times more common among blacks than whites, at least seventy percent of the participants in the study will be black. The pilot study will begin in the Spring of 1992 and continue for nearly three years. Upon completion of the pilot study, a decision will be made as to whether a full-scale study will be undertaken. The full-scale study would take an additional seven years to complete.

KIDNEY DISEASE OF DIABETES MELLITUS

Question. Can you tell us what research progress is being made on kidney disease of diabetes?

Answer. In 1987, the Institute began a major new initiative in "Kidney Disease of Diabetes Mellitus." As a result of this initiative, NIDDK funding in this area has increased about sixfold, from about $1.7 million in 1986 to approximately $10.6 million in 1990. In 1990, the Institute again increased funding for this area to sustain an initiative begun in 1987. New awards have been made, including one focused on kidney disease of diabetes mellitus (KDDM) in Native Americans. In addition, a new initiative on KDDM in Blacks with adult onset diabetes mellitus is being planned. Researchers have found that a reduction in blood pressure within the kidney may be one means to arrest kidney disease in diabetics. A new method for assessing kidney function has been developed by NIDDK-sponsored investigators. The method, measuring renal clearance using any one of three radioisotope markers is now being used to assess renal function in all current clinical trials and in the study of kidney disease in the Pima Indians. Institutesponsored animal studies have also shown that the progressive kidney damage often found in diabetics results from high blood pressure levels in the glomerulus. This research revealed that angiotensin-converting enzyme inhibitors, drugs that dramatically reduce glomerular blood pressure, can completely prevent glomerular disease and stabilize kidney disease once it has appeared. This finding, together with recent evidence supporting the value of a low-protein diet in lowering glomerular blood pressure, may represent a breakthrough in treating diabetics with kidney disease. Another group of NIDDK-supported scientists conducted a series of animal studies to learn more about the efficacy of antihypertensive therapy in reducing the progression of KDDM. They

determined that, while a general reduction in hypertension is beneficial in slowing the disease, a specific reduction in the blood pressure within the kidney is most effective in reducing the rate of KDDM progression. NIDDK grantees have also established that high blood glucose levels in poorly controlled diabetics may lead to enhanced water and sodium absorption in the kidney. These scientists believe that the molecular build-up may contribute to the hypertension and renal hypertrophy that characterize KDDM. This finding, coupled with recent reports that diabetics who have a family history of hypertension may experience a genetic predisposition to KDDM, provides significant clues about the cause and possible methods of preventing this life-threatening kidney disease of diabetes mellitus in the future.

CYSTIC FIBROSIS RESEARCH ADVANCES

Question. In your opening statement you briefly mentioned some recent progress that has been made in cystic fibrosis

research. What were some of the other significant advances made in this area during the past year, and what are the clinical implications of these findings?

Answer. It is indeed gratifying to the Institute to see that our broad support of cystic fibrosis research has produced some very exciting results. Other major advances in cystic fibrosis research this past year include reports by NIDDK grantees that direct correlations exist between CF gene defects and the clinical severity of CF, and that sophisticated techniques have been developed to visualize chloride transport, and defects thereof, under the microscope.

The continued expansion of fundamental knowledge about CF will hopefully lead to methods for bypassing the defective chloride ion channel regulation mechanism, to drugs that could alter the defective cystic fibrosis transmembrane regulator (CFTR) protein molecule, to gene therapy to replace the defective protein with a normal molecule, to improved diagnostic tests for the CF gene, and to techniques for replacing CFTR directly. We are confident that, ultimately, knowledge in these areas will translate into improved health for CF patients.

CYSTIC FIBROSIS RESEARCH EFFORTS

Question. We know the NIDDK is strongly committed to cystic fibrosis research, leading to an effective treatment, and hopefully the prevention, of this disease. What has your Institute done this past year to help progress toward these goals?

Answer. NIDDK and the Cystic Fibrosis Foundation jointly . issued a Request for Applications on the molecular basis of CF. The outstanding applications received in response to this solicitation will significantly expand the national research effort directed at CF. NIDDK also issued a "Cystic Fibrosis Core Center Grant" RFA in early 1990. NIDDK anticipated receipt of a competing continuation application from the existing Core Center, and invited other competing applications for a single Core Center grant to be awarded in Fiscal Year 1991. The existing Core Center at Case

Western Reserve Medical School was judged to be outstanding and will receive continued support.

The NIDDK supported a number of important conferences related to CF. The 1990 NIDDK "Fifth Annual Cystic Fibrosis Lecture Series: Recent Developments and New Trends in the Study of Cystic Fibrosis" brought leaders in CF research to NIH for a stellar series of lectures. NIDDK organized a workshop on "Current Issues in Screening for Cystic Fibrosis." The purpose of this workshop was to formulate a scientific statement to guide the introduction of carrier testing for cystic fibrosis into general medical practice. The statement developed was published in the New England Journal of Medicine: The NIDDK and the Cystic Fibrosis Foundation cosponsored a workshop "Drug Needs for Cystic Fibrosis" held at NIH on May 2, 1990, to foster interaction between academia and industry in developing new pharmaceutical approaches to the treatment of CF.

The NIDDK and the Cystic Fibrosis Foundation jointly sponsor a fellowship program that provides training, at the NIH, for qualified physicians in research careers relevant to cystic fibrosis. This program focuses on molecular genetics, ultrastructure, biochemistry, pharmacology, embryology of ion channels, mucins, and secretory processes.

CYSTIC FIBROSIS REQUEST FOR APPLICATIONS

Question. Your Institute released a Request for Applications this past year for research on cystic fibrosis. What were the results of this RFA?

Answer. In an innovative joint effort, the NIDDK and the Cystic Fibrosis Foundation solicited investigator-initiated research grant applications to define and characterize the molecular pathophysiology of cystic fibrosis. With the ultimate goal of developing effective new therapy for the disorder, the solicitation was intended to capitalize on the recent identification of the CF gene, the cystic fibrosis transmembrane regulator (CFTR) protein encoded by this gene, and the major mutation responsible for the defective function of this protein in CF.

A total of 63 applications were received in response to the RFA of which the NIDDK intends to fund 13 at an approximate total cost of $2.1 million in FY 1991. The Cystic Fibrosis Foundation will provide more limited funding for a similar number of meritorious grants beyond those to be funded by NIDDK. The applications to be funded were of very high quality and should contribute substantially to progress in understanding and treating cystic fibrosis.

Question. Judging from the response to your latest RFA for CF, and the fact that you are unable to fund many scientifically meritorious applications, it appears we are not taking full advantage of this country's research potential in this area. What is your assessment, and what are some of the scientific opportunities in cystic fibrosis research?